Drug addiction is a major problem in the world today. Addicts have severely disrupted circadian rhythms and there is an accumulating body of evidence that suggests that genes that control circadian rhythms might be involved in addiction. People who have genetic disruptions in circadian gene function are more prone to developing mood disorders such as bipolar disorder or seasonal affective disorder and these disorders are highly co-morbid with addiction. Furthermore, people with genetic sleep disorders involving the circadian clock are also more vulnerable to alcoholism and addiction. We also know from animal studies that drugs of abuse can entrain behavioral rhythms and molecular rhythms in key brain reward regions. This could lead to an anticipatory effect with increased craving and motivation to take drugs at a specific time of day. Other studies suggest that the loss of rhythms in drug intake is an important component in the transition from drug use to addiction. Though these studies are intriguing, still little is known about the molecular role of the circadian genes in the development of addiction. Genes that make up the molecular clock are expressed at high levels in the mesolimbic dopaminergic reward circuit between the ventral tegmental area (VTA) and nucleus accumbens (NAc). This entire reward circuit is under circadian control. It is likely that the regulation of dopaminergic transmission by the circadian genes is highly relevant to the development of addiction. Two proteins that regulate circadian rhythms, CLOCK and NPAS2, are very similar in sequence and function, however, they have different patterns of expression, and have different functions, within the VTA-NAc circuit. We have found that mice carrying a mutation in the Clock gene display an overall behavioral profile that is strikingly similar to human bipolar patients when in the manic state, including an increase in preference for cocaine. Interestingly, mice carrying a mutation in the Npas2 gene are similar in their responses when tested in behavioral measures of depression and anxiety, however, they have opposite phenotypes in measures of cocaine reward. In this proposal we will determine if expression of CLOCK and NPAS2 specifically in the NAc is important in the regulation of cocaine sensitization and reward. Furthermore, we will determine if reduction in CLOCK and NPAS2 function in the NAc changes the desire for cocaine self-administration, cocaine seeking after withdrawal, reinstatement of self-administration behavior after a cocaine challenge and the amount of work an animal is willing to put forward to get cocaine. To help determine a mechanism by which CLOCK and NPAS2 control these addiction-related behaviors, we will determine the full range of molecular targets that are regulated by these two transcription factors both at baseline conditions and following cocaine exposure. These studies will lead to a better understanding of how the circadian genes are involved in regulating the dopaminergic reward pathway and the development of cocaine addiction. PUBLIC HEALTH RELEVANCE: Substance abuse is a terrible problem in society today. Studies are beginning to identify an important role for the genes that control circadian rhythms in the development of addiction. The mechanism by which circadian genes influence drug reward may involve their regulation of the limbic dopaminergic circuit. Through these proposed experiments, we will determine if and how circadian gene expression in this circuit is important in modulating the behavioral responses associated with addiction. These studies will help us in developing potential treatments for addiction in the future.